CN115038467A - Method for preparing chitosan hydrogel-chelating agent for treating cancer - Google Patents
Method for preparing chitosan hydrogel-chelating agent for treating cancer Download PDFInfo
- Publication number
- CN115038467A CN115038467A CN202080095394.7A CN202080095394A CN115038467A CN 115038467 A CN115038467 A CN 115038467A CN 202080095394 A CN202080095394 A CN 202080095394A CN 115038467 A CN115038467 A CN 115038467A
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- cancer
- radionuclide
- chitosan hydrogel
- chelating agent
- chitosan
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Abstract
The present invention relates to a radioactive chitosan hydrogel-chelating agent, a method for preparing the same, and a composition for cancer treatment and embolization treatment containing the same as an active ingredient. According to the chitosan hydrogel-chelator for labeling radionuclides prepared in a size of 60 to 100 μm of the present invention, since it is used for embolization treatment of cancer tissue by blocking blood flow to tumor tissue and blocking oxygen and nutrient supply to tumor cells, it is particularly used for directly labeling radionuclides, which has excellent labeling efficiency and labeling stability, can minimize free radionuclides, and can expect not only therapeutic effects due to radionuclides but also therapeutic effects due to embolization, thereby improving therapeutic effects of lesions.
Description
Technical Field
The present invention relates to a method for preparing a chitosan hydrogel-chelating agent for treating cancer.
Background
In modern society, cancer-induced deaths continue to increase with the onset of cancer, early detection of cancer and the introduction of new therapeutics are imminent, and new surrogates for treating extreme conditions of cancer, but also for treating incurable diseases, are urgently needed.
The method for treating incurable diseases including cancer using radionuclide is very simple and economical compared to surgery, and most importantly, not only can relieve pain given to patients but also has high therapeutic effect. Therefore, therapeutic methods using radionuclides are widely used. However, the therapeutic method using radionuclides has a disadvantage of destroying normal cells by affecting diseased sites and normal tissues.
In order to solve the above problems, it is important to design a biocompatible polymer so that tissue is selectively destroyed only at a disease site where a radionuclide is injected, and the radionuclide is prevented from migrating to other normal sites. The biocompatible polymer containing the radionuclide to be administered preferably releases radiation at a diseased site, and when a sufficient time has elapsed, it is biodegraded, absorbed, and excreted.
As a local therapeutic agent using a radionuclide currently used, there is a local therapeutic agent using Sirtex corporation 90 A therapeutic agent for liver cancer comprising Y SIR microspheres, which is useful for the treatment of patients with liver cancer who are not susceptible to surgical removal. And is known to utilize the same of the chemical industry Co., Ltd 166 Complexes of holmium and chitosan( 166 Ho-chitosan) can necrotize cancer cells in a short time by only 1 injection, thereby being useful for the treatment of small-sized liver cancer. In addition, as radionuclides, there are 186 Re-tin colloid, 186 Re-sulfur colloid, 188 Re-hydroxyapatite, 90 Y-colloids, and the like. Further, a polymer containing a particulate radionuclide, a preparation method thereof, and a kit for preparing the same are described in Korean patent laid-open publication No. 10-530276, a composition for treating prostate cancer containing a radioactive substance-chitosan complex, and a kit for preparing the composition are described in Korean patent laid-open publication No. 10-530276, and a radioactive substance-chitosan complex solution composition for improving gelation stability during in vivo injection, and a preparation method thereof are described in Korean patent laid-open publication No. 10-2006-60970. However, when a therapeutic agent containing the above-mentioned radionuclide is administered to a lesion in the form of an aqueous solution, a part of the therapeutic agent leaks out of the tissue, and a side effect of destroying the normal tissue occurs, and the therapeutic agent flows to other sites without being retained at the site of administration, or only water is absorbed by the tissue after administration, and the radionuclide is precipitated and accumulated on one side, resulting in a problem of uneven irradiation, and the like, and thus the form of the radioactive particles may be unsuitable for treatment.
Among the above-mentioned radioactive nuclides, those mentioned above, 166 the Ho-chitosan complex becomes a gel in vivo after injection in the form of an aqueous solution, and remains in the form of a lesion site, and therefore has an advantage of being irradiated with radiation accurately and uniformly as compared with a radionuclide existing in the form of a solution. Further, there is an advantage that not only the radioactivity is removed but also the chitosan liquid administered together in a complex state is decomposed and disappears after a sufficient time has elapsed. And the number of the first and second electrodes, 166 ho is also less expensive than other radionuclides. However, it is possible to prevent the occurrence of, 166 the aqueous solution of the Ho-chitosan complex has a disadvantage that it is an acidic solution, and has a problem that it is not easily gelled to cause the radionuclide to be released to the normal tissue. And, comprise 166 Ho or 90 Y has half-lives of 26.9 hours and 641 hours, respectively, and is useful for preparing therapeutic agentsThe treatment agent needs to be prepared on site.
Also, embolization therapy (embolization) or embolization is a treatment method characterized in that, in order to regulate bleeding or treat tumors, a specific substance (e.g., a balloon) is injected into an artery through a catheter to selectively block a blood vessel. Substances used in such embolotherapy prevent blood flow to the tumor tissue and block the supply of oxygen and nutrients to the tumor cells or regulate bleeding.
Such a composition for embolization preferably has biocompatibility (biocompatible) and hydrophilicity, particularly needs to have a predetermined size for the purpose, is useful for occlusion of blood vessels because of its spherical shape, needs to minimize irritation of blood vessels, has elasticity or flexibility at a predetermined level or more for occluding blood vessels, and preferably swells at a predetermined level or more so as to be capable of being administered through a narrow tube and then swells to occlude blood vessels.
Therefore, there is an urgent need for the related development necessity of therapeutic agents using radionuclides that gel smoothly and can minimize the release of radionuclides to normal tissues.
Disclosure of Invention
Technical problem
The present invention is directed to a method for preparing a chitosan hydrogel-chelator for labeling radionuclides.
It is another object of the present invention to provide a radionuclide-labeled chitosan hydrogel-chelating agent prepared by the above method.
It is another object of the present invention to provide a pharmaceutical composition for cancer treatment, which comprises a chitosan hydrogel-chelating agent labeled with the above radionuclide.
It is another object of the present invention to provide a pharmaceutical composition for treating embolism, which comprises a chitosan hydrogel-chelating agent labeled with the above radionuclide.
Technical scheme
In one embodiment of the present invention for achieving the above objects, there is provided a method for preparing a chitosan hydrogel-chelating agent labeled with radionuclide, comprising:
1) electrospinning chitosan and a crosslinking substance to prepare a chitosan hydrogel;
2) a step of reacting the chitosan hydrogel prepared in the step 1) with a chelating agent having a functional group capable of labeling a radionuclide to prepare a chitosan hydrogel-chelating agent,
the chelating agent is at least one selected from the group consisting of N-succinimidyl-3- (4-hydroxyphenyl) propionate, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid, diethylenetriaminepentaacetic acid, histidine, tyrosine and a protein containing tyrosine;
3) reacting the chitosan hydrogel-chelating agent prepared in the step 2) with a radionuclide and an active agent for labeling the radionuclide.
The above step 1) is a step of forming a chitosan hydrogel, and the hydrogel is prepared by reacting biodegradable chitosan with a crosslinking substance. In the preparation of the above hydrogel, the particle size effective for embolization therapy can be adjusted by adjusting the concentration of chitosan, radiation voltage, flow rate, radiation, etc. In a specific embodiment, the particle size may be 60 μm to 100 μm.
In the preparation of the hydrogel, as the concentration of chitosan increases, the density of the hydrogel to the particles increases, and the particles become firm and the stability of the particles increases. The size and uniformity of particles in embolization therapy are factors directly linked to the therapeutic effect, and by increasing the concentration of chitosan, particles of uniform size can be produced.
The above-mentioned cross-linking substance is used for forming a hydrogel, and when the hydrogel is prepared by using the substance, the labeling stability of the radionuclide is increased, and the radionuclide can be prevented from flowing out to normal tissues outside the focal site. The crosslinking agent may be 1 or more selected from the group consisting of tripolyphosphate, alginic acid, pectin, carboxymethyl cellulose, polyglutamic acid, protein, DNA and RNA, but is not limited thereto. The crosslinking substance may be an anionic crosslinking substance, but is not limited thereto.
In the electrospinning process, electrospinning can be performed at a voltage of 1kV to 20kV and a flow rate of 0.01mL/min to 0.05 mL/min. In a specific embodiment, electrospinning can be performed at a voltage of 10kV to 12kV and a flow rate of 0.01mL/min to 0.03 mL/min.
The above-mentioned step 2) is a step of preparing the chitosan hydrogel-chelating agent, which is a step of mixing the chitosan hydrogel particles with a chelating agent dissolved in an organic solvent to obtain the chitosan hydrogel-chelating agent.
The chelating agent is a compound having a functional group capable of labeling a radionuclide, and is at least one selected from the group consisting of N-succinimidyl-3- (4-hydroxyphenyl) propionate, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid, diethylenetriaminepentaacetic acid, histidine, tyrosine, and a protein containing tyrosine, but is not limited thereto.
The above-mentioned radionuclide is selected from 131 I、 125 I、 124 I、 186 Re、 188 Re、 90 Y、 166 Ho、 99m Tc and 177 at least one element selected from the group consisting of Lu, but not limited thereto.
The radionuclide may be different depending on the kind of the chelating agent.
For example, when the chelating agent is N-succinimidyl-3- (4-hydroxyphenyl) propionate, the radionuclide is preferably selected from the group consisting of 131 I、 125 I and 124 1 or more of group I.
And, when the chelating agent is 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid, the radionuclide is preferably 177 Lu。
And, when the chelating agent is diethylenetriaminepentaacetic acid, the radionuclide is preferably selected from 186 Re、 188 Re and 99m tc is 1 or more of the group.
In the step 3), the active agent for labeling the radionuclide is preferably any one selected from the group consisting of chloramine T, a mixture of ascorbic acid and gentisic acid, and tin (ii) chloride.
In particular, the above-mentioned step 3) is a step of preparing a chitosan hydrogel-chelating agent for labeling a radionuclide, in which a radionuclide is added to the chitosan hydrogel-chelating agent and reacted with an active agent for labeling a radionuclide, to obtain a chitosan hydrogel-chelating agent for labeling a radionuclide. In the chitosan hydrogel-chelating agent labeling the above radionuclide, the labeling rate of the radionuclide is 99%.
When the concentration of chitosan is excessively increased in order to improve the stability of the chitosan hydrogel, it is difficult to mix the chitosan solution and a reactant for labeling radionuclides (e.g., radionuclide, buffer, reducing agent) due to the high viscosity of chitosan, and a precipitate may be generated.
And, when chitosan hydrogel-chelator labeled radionuclide formulated by synthesizing chelator from chitosan, has low labeling efficiency of less than 5%.
Since the labeling yield of the radionuclide to the chitosan hydrogel-chelating agent is 20% to 40% higher than that of the radionuclide to the chitosan-chelating agent, it is advantageous in terms of the labeling yield of the radionuclide.
The chitosan hydrogel-chelating agent is advantageous in that since chitosan hydrogel particles are dispersed in a diluted reaction solution, and reactants are mixed to synthesize a chelating agent and label a radionuclide, the process of labeling a high-concentration polymer solution is simplified, contamination due to the radionuclide can be reduced, and the labeling yield can be increased compared to the case of labeling a radionuclide in a chitosan hydrogel-chelating agent.
Further, although it takes about 10 days to prepare the chitosan-chelator through the dialysis and freeze-drying processes, it takes less than 1 day to prepare the chelator when the chitosan hydrogel is synthesized, so that the preparation time can be shortened, and the selection of the chelator according to the radionuclide to be labeled in the state of the chitosan hydrogel can be widened.
Therefore, the chitosan hydrogel-chelator manufacturing method can be more flexibly applied to radionuclide labeling than the chitosan-chelator manufacturing method, and the chitosan hydrogel particles are easier to handle than the chitosan solution, so that efficient labeling of radionuclides can be expected, and are safer in terms of radiation contamination and radiation exposure.
That is, according to the present invention, the preparation of the chitosan hydrogel-chelating agent and the labeling of the radionuclide are performed based on the preparation of the chitosan hydrogel preferentially after the preparation of the chitosan hydrogel, thereby having advantages of not only being able to label the radionuclide with high efficiency and stability but also significantly shortening the time in the preparation process elegantly.
Moreover, the preparation method may further include:
4) a step of purifying the hydrogel prepared in the step 3) above using a polymer network. The above-mentioned step 4) is a purification step of the hydrogel using a polymer network, and by this step, impurities such as reaction raw materials such as an unreacted crosslinking agent and the like and crushed particles are removed, and a high-purity chitosan hydrogel-chelating agent can be prepared.
The mesh size of the polymer network is smaller than the particle size of the hydrogel to be prepared, and the reaction material, the pulverized particles, and the like can easily pass through, and preferably 50 μm.
The polymer may be nylon mesh (nylon mesh), polyester (polyester), polypropylene (polypropylene), polyethylene (polyethylene), polycarbonate (polycarbonate), polytetrafluoroethylene (polytetrafluoroethylene), polyamide-imide (polyamide-imide), polyphenylene sulfide (polyphenylene sulfide), and preferably, nylon mesh.
The above-mentioned step 4) is a step of performing a purification process using a polymer network, and in the steps 1) to 3), is used for a purification process of removing impurities and reactants except the chitosan hydrogel, the chitosan hydrogel-chelating agent, and the chitosan hydrogel-chelating agent labeled with radionuclide.
In another embodiment of the present invention for achieving the above objects, there is provided a chitosan hydrogel-chelating agent labeled with radionuclide prepared by the above method.
In another embodiment of the present invention, there is provided a chitosan hydrogel-chelating agent labeling a radionuclide, including: a chitosan hydrogel combined with a chelating agent having a functional group capable of labeling a radionuclide; and a radionuclide linked to the functional group. Wherein the radionuclide, the functional group, and the chelating agent are as described above. A chelating agent having a functional group capable of labeling a nuclide, chemically bound to the chitosan hydrogel, the functional group capable of binding to the nuclide, thereby providing a chitosan hydrogel-chelating agent that labels the radionuclide.
The binding of the chitosan hydrogel to the chelating agent having a functional group capable of labeling a radionuclide has advantages in terms of a preparation method and therapeutic effects, compared to the conventional method in which the chelating agent having each functional group is reacted with the chitosan hydrogel under appropriate solvent conditions, and the chelating agent having a functional group capable of labeling a radionuclide is bound to chitosan and the hydrogel is bound thereto.
In terms of preparation, because the radionuclide does not need to be electrospun during preparation, the condition of irradiating preparation personnel with the radionuclide can be reduced, and the pollution of preparation equipment can be reduced.
On the other hand, since the radiochemical stability after labeling is high in terms of treatment, side effects due to free radionuclides can be reduced, and the safety of a subject can be ensured by ensuring the stability of the radionuclides. Also, the amount of radioactivity labeled can be predicted and adjusted, and the exact amount of radioactivity required can be dosed per unit of chitosan hydrogel, thereby facilitating quantification.
The hydrogel of the present invention can be administered with 0.5-150 mCi/mass 1cm per time according to the type of disease and the size of the disease focus 3 Preferably, 0.5 to 50 mCi/lump of 1cm can be added 3 。
When the chitosan hydrogel-chelating agent prepared by the above method is locally and directly injected into a cancer tissue site, the hydrogel remains in the cancer tissue site, hardly flows out to the outside, and prevents blood from flowing into a tumor tissue to block oxygen and nutrients from being supplied to tumor cells, thereby causing necrosis of the cancer tissue.
As described above, the chitosan hydrogel-chelator according to the present invention directly labels a radionuclide in chitosan, has excellent labeling efficiency and labeling stability of the radionuclide, minimizes the amount of free radionuclide, allows local direct injection into a lesion site, stably remains in the lesion site, and emits radiation, and thus can be usefully used for the treatment of incurable diseases such as cancer. Therefore, the chitosan hydrogel-chelating agent of the present invention is expected to have not only an embolic treatment effect but also a therapeutic effect due to radionuclides, thereby improving the therapeutic effect of the lesion.
The above-mentioned preparation method is a method for preparing a hydrogel-chelating agent using chitosan at a high concentration, and has an advantage that the possibility of outflow to other organs is low because the density of particles is high and thus it is advantageous in terms of stability when injected into the body, and the durability of particles is high, as compared with the preparation method for preparing a chitosan-chelating agent hydrogel using chitosan at a low concentration. In addition, since the stability of the labeled radionuclide is also high, side effects such as thyroid uptake of free I-131 are reduced. In addition, in the hydrogel having a large particle size range to be prepared, when large particles are injected first, the particles block blood vessels before reaching the lesion, but since the particle size is relatively uniformly prepared using high-concentration chitosan, the probability of reaching the target lesion is high, and thus a higher therapeutic effect can be expected.
The particle size of the hydrogel is one of the most important factors in the therapeutic effect. The results of experiments relating to medium-sized animals having a size similar to that of human hepatic artery blood vessels, for example, rabbit hepatic artery, show that hydrogel having a particle size of 60 to 100 μm has the injected particles positioned at the same location as the tumor site, whereas hydrogel having a particle size of 100 to 300 μm has the injected particles positioned outside the tumor, and thus the therapeutic effect of the lesion may be improved by hydrogel particles having a particle size of 60 to 100 μm. Therefore, experiments relating to animals in liver cancer were carried out using hydrogel particles of 60 μm to 100 μm, which can be expected to have a good therapeutic effect.
In another embodiment of the present invention for achieving the above objects, there is provided a pharmaceutical composition for cancer treatment comprising the chitosan hydrogel-chelating agent labeled with the above radionuclide.
In the present invention, the term "treatment" means an action of causing cancer to heal by administration of the above-mentioned composition, and is intended to improve the treatment, alleviation, relief, therapy (remedy) of a disease, a symptom of a disease, a secondary disease of a disorder or a disease, or a predisposition (predisposition) associated therewith, or is defined as a case of applying or administering a composition comprising the above-mentioned nanoparticles to a subject (human or animal) suffering from a disease, a symptom of a disease, a secondary disease of a disorder or a disease, or a predisposition (human or animal) associated therewith.
The cancer may be 1 or more selected from the group consisting of liver cancer, lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, cutaneous melanoma, uterine cancer, ovarian cancer, rectal cancer, large intestinal cancer, colon cancer, breast cancer, uterine sarcoma, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, esophageal cancer, small intestinal cancer, thyroid cancer, sarcoma of soft tissue, cancer of the urethra, penile cancer, prostate cancer, chronic or acute leukemia, solid tumor in juvenile stage, differentiated lymphoma, bladder cancer, kidney cancer, renal cell carcinoma, renal pelvis cancer, first central nervous system lymphoma, cerebrospinal tumor, brain stem glioma and pituitary tumor, but is not limited thereto.
The pharmaceutical composition of the present invention may further comprise a pharmaceutically acceptable carrier, excipient or diluent which is generally used in the preparation of pharmaceutical compositions, and the carrier may comprise a non-naturally occurring carrier.
The pharmaceutical compositions can be formulated into oral dosage forms such as powder, granule, tablet, capsule, suspension, emulsion, syrup, and aerosol, external preparations, suppositories, and sterile injection solutions according to conventional methods.
The above "pharmaceutically acceptable" means exhibiting the property of not being toxic to cells or humans exposed to the above composition.
Specifically, the kind of the carrier is not particularly limited, and any carrier can be used as long as it is pharmaceutically acceptable as is generally used in the art. As non-limiting examples of the above-mentioned carrier, saline, sterilized water, ringer's solution, buffered saline, albumin injection solution, dextrose solution, maltodextrin solution, glycerol, ethanol and the like can be cited. They may be used alone or in combination of 2 or more. If necessary, other conventional additives such as antioxidants, buffers and/or bacteriostats may be added and used, and diluents, dispersants, surfactants, binders, lubricants and the like may be added to the composition to prepare injection preparations such as aqueous solutions, suspensions and emulsions, and dosage forms such as pills, capsules, granules and tablets.
The administration mode of the pharmaceutical composition for cancer treatment according to the present invention is not particularly limited and may be varied according to the modes generally used in the art. As a non-limiting example of the above administration, the administration can be carried out by oral administration or parenteral administration. Also, the composition for cancer amelioration or treatment of the present invention may be prepared in various dosage forms according to the intended administration mode.
The term "improve" in the present invention refers to all actions that at least reduce the extent of a condition-related parameter, such as a symptom, treated by administration of a composition of the present invention.
The above composition can be used alone or in combination with methods using surgery, hormonal therapy, drug therapy and biological response modifiers for the treatment of cancer. Preferably, the composition is in the form of an injection, but is not limited thereto. Compositions of the present invention for parenteral administration include sterile aqueous or non-aqueous liquid agents, dispersions, suspensions or emulsions as well as sterile powders for reconstitution prior to use as sterile liquid agents or suspensions. Examples of suitable sterile aqueous and nonaqueous carriers, diluents, solvents or vehicles are water, physiological saline, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, and the like) and mixtures thereof, vegetable oils (e.g., olive oil), injectable organic esters (e.g., ethyl oleate). For example, a coating material such as lecithin is used as a dispersing agent or a suspending agent, and a surfactant is used to maintain a proper specific size and a proper fluidity. Also, the parenteral composition may contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Sterilization of the injectable form is carried out, for example, by filtration through a sterilizing filter, or the components of the mixture may be sterilized beforehand, either before preparation or before administration (as in the case of double container syringe packaging).
In another embodiment of the present invention for achieving the above objects, there is provided a composition for the treatment of embolism, comprising a chitosan hydrogel-chelating agent labeled with a radionuclide.
Embolization therapy (embolization) is a therapeutic method for regulating bleeding or selectively blocking blood vessels by injecting a specific substance into an artery in order to treat tumors, and the chitosan hydrogel-chelating agent according to the present invention prevents blood from flowing to tumor tissues, thereby blocking the supply of oxygen and nutrients to cells.
The above composition can be injected through hepatic artery, and preferably, can be used for embolization treatment of liver cancer tissue.
In another embodiment of the present invention for achieving the above objects, there is provided a method for preventing or treating cancer in a subject comprising the step of administering the chitosan hydrogel-chelating agent labeled with the above radionuclide to a subject in need thereof.
In another embodiment of the present invention for achieving the above objects, there is provided an embolismus preventing or treating method for a subject including the step of administering a chitosan hydrogel-chelating agent labeled with the above radionuclide to a subject in need thereof.
The subject body or subject refers to an animal, and typically may be a mammal which may exhibit a beneficial effect by treatment with the above-described composition of the present invention. Preferred examples of such a subject include a human primate. Also, such subjects may include subjects at risk of or suffering from symptoms of cancer or embolism.
The invention also provides the use of the chitosan-hydrogel chelating agent described above in the preparation of a medicament for the treatment of cancer.
The invention also provides the use of the chitosan-hydrogel chelating agent described above in the preparation of a medicament for the treatment of an embolism.
The present invention also provides a composition comprising the above chitosan-hydrogel chelating agent for use in cancer treatment.
The present invention also provides a composition comprising the chitosan-hydrogel chelating agent described above for use in the treatment of embolisms.
Repetitive matters are omitted in consideration of the complexity of the present specification, and terms not particularly defined in the present specification have meanings commonly used in the art to which the present invention belongs.
ADVANTAGEOUS EFFECTS OF INVENTION
The chitosan hydrogel-chelator according to the present invention can directly label a radionuclide onto a biodegradable polymer hydrogel, has excellent labeling efficiency, yield, and labeling stability of the radionuclide, can minimize the amount of free radionuclide, can be locally injected directly into a lesion site, can stably remain in the lesion site, and can release radiation, and can be usefully used for the treatment of incurable diseases such as cancer. Therefore, according to the chitosan hydrogel-chelating agent of the present invention, not only treatment by radionuclides but also therapeutic effect by embolization can be expected at the same time, thereby improving therapeutic effect of lesions.
Drawings
Fig. 1 shows a chitosan hydrogel prepared from 1% or 2% chitosan using an optical microscope.
Fig. 2 shows the chitosan hydrogel prepared according to the modification of the electrospinning conditions by using an optical microscope.
FIG. 3 shows the labeling efficiency of the chitosan hydrogel at the chitosan hydrogel-SHPP marker I-131.
FIG. 4 shows the labeling efficiency of chitosan hydrogel labeled Lu-177 at chitosan hydrogel-DOTA.
FIG. 5 shows the labeling efficiency of chitosan hydrogel labeled Tc-99m at chitosan hydrogel-DTPA.
FIG. 6 shows the stability of the label against I-131 of chitosan hydrogel-SHPP as determined by radiochemical foreign assay.
FIG. 7 shows the label stability against I-131 of chitosan hydrogel-SHPP as determined by the leaching test.
In FIG. 8, the evaluation of the particle distribution of the Tc-99m labeled chitosan hydrogel-DTPA was performed on a rabbit liver cancer model.
FIG. 9 shows the labeling yields for I-131 of chitosan-SHPP (A) and chitosan hydrogel-SHPP (B).
FIG. 10 shows CT images of animal models in liver cancer treated with chitosan hydrogel-SHPP prepared from particle sizes of 60 μm to 100 μm.
FIG. 11 is a graph showing the results of measuring the tumor volume of the liver cancer model of the middle animal for 4 weeks.
FIG. 12 is a graph showing the results of treating an animal model in liver cancer with chitosan hydrogel-SHPP prepared from a particle size of 60 μm to 100 μm and measuring the weight of tumor.
Fig. 13 graphically shows the correlation between the results of comparing the weight and volume of the tumor.
Best mode for carrying out the invention
Examples and Experimental examples
The present invention will be described in more detail below with reference to examples. However, the examples are merely illustrative of the present invention, and the scope of the present invention is not limited to these examples.
Example 1 preparation of Chitosan hydrogel
(1) Preparation of 1% Chitosan hydrogel
After 25mg of chitosan was dissolved (1%) in 2.5mL of 0.1M acetic acid, a hydrogel was prepared by electrospinning at a voltage of 1kV to 20kV using a solution in which 5g of sodium Tripolyphosphate (TPP) was dissolved by a pump.
(2) Preparation of 2% Chitosan hydrogel
After 50mg of chitosan was dissolved (2%) in 2.5mL of 0.1M acetic acid, a hydrogel was prepared by electrospinning at a voltage of 1kV to 20kV using a solution in which 5g of sodium Tripolyphosphate (TPP) was dissolved by a pump.
Example 2 preparation of Chitosan hydrogel-chelating agent
(1) Synthesis of chitosan hydrogel-SHPP
After purifying the chitosan hydrogel using a polymer network, 10mg of N-succinimidyl-3- (4-hydroxyphenyl) propionate (hereinafter, SHPP) dissolved in DMF or DMSO was added and reacted for 6 hours or more. The chitosan hydrogel-SHPP prepared above is purified by using a polymer network.
(2) Synthesis of chitosan hydrogel-DOTA
After purifying the chitosan hydrogel by using a polymer network, 10mg of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid, DOTA below) dissolved in DMF or DMSO was added and reacted for 6 hours or more. Purifying the prepared chitosan hydrogel-DOTA by using a polymer network.
(3) Synthesis of chitosan hydrogel-DPTA
After purifying the chitosan hydrogel using a polymer network, 10mg of diethylenetriamine pentaacetic acid (DTPA) dissolved in distilled water and methanol were added and reacted for 6 hours or more. Purifying the prepared chitosan hydrogel-DTPA by using a polymer network.
Example 3 preparation of Chitosan hydrogel-chelating agent for labeling radionuclides
(1) Labeling radioactive iodine (I-131) on chitosan hydrogel-SHPP
The chitosan hydrogel-SHPP prepared in (1) of example 2 above was reacted for 1 hour with radioiodine (I-131) and chloramine-T (2mg/0.1mL phosphate buffer (pH 7.5)). After the reaction was completed, purification was performed using a polymer network to obtain chitosan hydrogel-SHPP labeled with radioactive iodine (I-131).
The chitosan hydrogel-SHPP prepared in 1 of example 2 above was reacted for 1 hour with radioiodine (I-131) and chloramine-T (2mg/0.1mL phosphate buffer (pH 7.5)). After the reaction was completed, purification was performed using a polymer network to obtain chitosan hydrogel-SHPP labeled with radioactive iodine (I-131) of the following reaction formula 1.
[ reaction formula 1]
(2) Labeling Lu-177 in chitosan hydrogel-DOTA
Lu-177, ascorbic acid and gentisic acid were added to the chitosan hydrogel-DOTA prepared in (2) of example 2, and the mixture was reacted at 80 ℃ for 30 minutes. After the reaction was completed, purification was performed using a polymer network to obtain Lu-177-labeled chitosan hydrogel-DOTA as in the following reaction formula 2.
(3) Marking Tc-99m on chitosan hydrogel-DTPA
The chitosan hydrogel-DTPA prepared in (3) of the above example 2 was added with Tc-99m and stannous chloride (tin (ii) chloride) dissolved in distilled water from which dissolved oxygen was removed, and reacted for 30 minutes. After the reaction was completed, purification was performed using a polymer network to obtain chitosan hydrogel-DTPA labeled with Tc-99m as in the following reaction formula 3. And, the chitosan hydrogel-DTPA can be labeled by the same method 186 Re and 188 Re。
experimental example 1 particle size and morphology comparison experiment based on chitosan concentration
In order to compare and analyze the particle size and morphology of the chitosan hydrogel prepared in (1) of example 1 and (2) of example 1, the following experiment was performed. Specifically, each chitosan hydrogel was observed and evaluated at 40 magnifications using an optical microscope, and the results thereof are shown in fig. 1.
As shown in fig. 1, when prepared from a 2% chitosan hydrogel (right side), it was confirmed that particles were produced having a smooth spherical shape, a high particle density, and more uniform particle morphology, compared to when prepared from a 1% chitosan hydrogel (left side).
Experimental example 2 particle size of chitosan hydrogel was adjusted by varying electrospinning conditions
As shown in (2) of the above example 1, in order to adjust the particles of the hydrogel for 2% of chitosan, the following experiment was performed. Specifically, the particle size was evaluated by varying the voltage regulation and the flow rate regulation. It was confirmed that particles having an average particle size of 150 were produced at a voltage of 10kV and a flow rate of 0.03mL/min (left), and particles having an average particle size of 70 μm were produced at a voltage of 11kV and a flow rate of 0.01mL/min (right), and the results are shown in FIG. 2.
Experimental example 3 measurement of labeling efficiency of chitosan hydrogel-chelating agent labeling radionuclide
As shown in example 3, the results of measurement of the labeling efficiency by ITLC using the radioactive-TLC scanning method using the chitosan hydrogel-SHPP label I-131, the chitosan hydrogel-DOTA label Lu-177, and the chitosan hydrogel-DTPA label Tc-99m are shown in fig. 3, 4, and 5, respectively.
It was confirmed that the labeling efficiency of the chitosan hydrogel-SHPP labeled I-131 (upper) was 99.8%, that of the chitosan hydrogel-DOTA labeled Lu-177 (middle) was 98.0%, and that of the chitosan hydrogel-DTPA labeled with Tc-99m (lower) was 99.5%.
EXPERIMENTAL EXAMPLE 4 determination of the stability of the marking by radiochemical foreign bodies of chitosan hydrogel-chelating agents marking radionuclides
As shown in experimental example 3, the chitosan hydrogel-SHPP labeled with radioactive iodine (I-131) prepared as described in (1) of example 3 was subjected to an 8-day radiochemical foreign substance test to evaluate the labeling stability of I-131 against the chitosan hydrogel-SHPP, and the results are shown in fig. 6.
As a result of measurement by the radiochemical foreign substance test, it was confirmed that the labeled radioiodine (I-131) was stably maintained in the chitosan hydrogel-SHPP at 97.88% or more for 8 days.
EXPERIMENTAL EXAMPLE 5 determination of Label stability by leaching test of Chitosan hydrogel-chelating agent labeled with radionuclide
The chitosan hydrogel-SHPP labeled with radioactive iodine prepared as described in (1) of example 3 was subjected to an 8-day leaching test to evaluate the labeling stability of I-131 against the chitosan hydrogel-SHPP, and the results thereof are shown in fig. 7.
From the results of the leaching test, it was confirmed that the labeled radioiodine (I-131) was stably maintained at 95.22% or more for 8 days in the chitosan hydrogel-SHPP.
Experimental example 6 evaluation of distribution of lesion site based on size of chitosan particle
As shown in Experimental example 2, DTPA as a chelating agent was synthesized on chitosan hydrogel prepared from 60 μm to 100 μm (average 70 μm) and 100 μm to 300 μm (average 150 μm), Tc-99m as a radioisotope was labeled, and Tc-99 m-labeled chitosan hydrogel-DTPA was prepared. Then, two kinds of Tc-99m chitosan hydrogel-DTPA (average 70 μm and 150 μm) with different labeled particle sizes were injected into the middle animal (rabbit) liver cancer model, and the particle distribution of the middle animal liver cancer model was evaluated, and the results are shown in fig. 8.
It was confirmed that particles of 150 μm on average were not close to the lesion of the tumor and distributed outside the tumor due to the size of blood vessels outside the tumor, and particles of 70 μm on average were distributed at positions sufficiently effective for the treatment with the radionuclide in accordance with the lesion of the tumor. Although the embolization effect was confirmed by the particles staying in the external blood vessels of the tumor in experimental example 6, the embolization effect and the radiation effect were confirmed by the modified particles only once, since the effect of tumor therapy by the effect of radiation emitted from I-131 was very slight, as long as the particles were uniformly distributed around the outside of the tumor lesion, which is a region where the tumor growth is vigorous.
EXAMPLE 7 evaluation of labeling yield of radioiodine (I-131) against Chitosan-SHPP and Chitosan hydrogel-SHPP
The labeling yields of chitosan-shpp (a) labeled with radioactive iodine and chitosan hydrogel-shpp (b) labeled with radioactive iodine (I-131) prepared as in (1) of example 3 are shown in fig. 9.
The labeling yield of group A was 26.93. + -. 7.70%, the labeling yield of group B was 65.50. + -. 9.64%, and the labeling yield of group B was 38.57% higher than that of group A, confirming that the labeling method for I-131 of chitosan hydrogel-SHPP was more effective in yield than the labeling method for I-131 of chitosan-SHPP.
Experimental example 8 evaluation of the therapeutic Effect of Chitosan hydrogel-SHPP in the animal liver cancer model by CT image
In experimental example 2, an animal model of liver cancer was treated with chitosan hydrogel-SHPP prepared with a particle size of 60 μm to 100 μm, and the therapeutic effect was evaluated by CT images, and the results are shown in fig. 10.
An increase in contrast and an increase in tumor size were observed at the tumor margin within 2 weeks in the control group (upper) without any treatment, and a decrease in contrast size was observed at the tumor margin within 2 weeks in the chitosan hydrogel-SHPP-treated group (lower). Therefore, the treatment effect of the chitosan hydrogel-SHPP can be confirmed in a liver cancer model of a middle animal.
EXAMPLE 9 evaluation of the therapeutic Effect of Chitosan hydrogel-SHPP in the animal liver cancer model by measuring the tumor volume
The volume of the tumor was measured for 4 weeks in the CT image of the middle animal liver cancer model of experimental example 8, and the results are shown in fig. 11.
A linear increase in tumor volume was confirmed in the control group, whereas a decrease in tumor size with the passage of time was confirmed in the chitosan hydrogel-SHPP-treated group.
Experimental example 10 evaluation of the therapeutic Effect of Chitosan hydrogel-SHPP in the animal liver cancer model by measuring the tumor weight
In experimental example 2, the weight of the tumor was measured using an animal model in which the chitosan hydrogel-SHPP prepared with a particle size of 60 to 100 μm was used to treat the liver cancer, and the therapeutic effect was evaluated, and the results are shown in fig. 12.
The weight of the tumor in the control group was 20.8. + -. 3.8g, and the weight of the tumor in the chitosan hydrogel-SHPP-treated group was 2.2. + -. 0.6g, whereby the therapeutic effect was confirmed by reducing the tumor weight.
Experimental example 11 evaluation of correlation between tumor weight and volume
The results of comparing the results of the weight and volume of the tumor measured in experimental example 9 and experimental example 10 were evaluated for correlation, and the results are shown in fig. 13.
In the case of the control group, the tumor weight and volume showed a linear relationship and tumor growth was confirmed, and in the case of the chitosan hydrogel-SHPP, the tumor was treated and the correlation of the tumor weight and volume was confirmed to disappear.
As described above, the present invention is illustrated by examples. Those skilled in the art to which the present invention pertains will appreciate that the present invention can be implemented in other specific embodiments without changing the technical idea or essential features of the present invention. Therefore, it should be understood that the above-described embodiments are illustrative in all respects, not restrictive. The scope of the present invention is shown by the appended claims, not by the detailed description, and should be construed to include all modifications or variations derived from the meaning and scope of the claims and equivalent concepts.
Claims (22)
1. A method for preparing a chitosan hydrogel-chelator for labeling radionuclides, comprising:
1) electrospinning chitosan and a crosslinking substance to prepare a chitosan hydrogel;
2) a step of reacting the chitosan hydrogel prepared in the step 1) with a chelating agent having a functional group capable of labeling a radionuclide, to prepare a chitosan hydrogel-chelating agent, the chelating agent being any one or more selected from the group consisting of N-succinimidyl-3- (4-hydroxyphenyl) propionate, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid, diethylenetriaminepentaacetic acid histidine, tyrosine, and a protein including tyrosine;
3) reacting the chitosan hydrogel-chelating agent prepared in the step 2) with a radionuclide and an active agent for labeling the radionuclide.
2. The method of claim 1, wherein the cross-linking agent is at least one selected from the group consisting of tripolyphosphate, alginic acid, pectin, carboxymethyl cellulose, polyglutamic acid, protein, DNA, and RNA.
3. The method of claim 1, wherein the electrospinning is performed at a voltage of 1kV to 20kV and a flow rate of 0.01mL/min to 0.05 mL/min.
4. The method of preparing a chitosan hydrogel-chelator for labeling radionuclides as in claim 1, further comprising:
4) a step of purifying the hydrogel prepared in the step 3) using a polymer network.
5. The method for preparing a chitosan hydrogel-chelator for labeling radionuclides as in claim 1, wherein the radionuclide is selected from the group consisting of 131 I、 125 I、 124 I、 186 Re、 188 Re、 90 Y、 166 Ho、 99m Tc and 177 more than 1 of Lu.
6. The method of claim 1, wherein the active agent for labeling the radionuclide is any one selected from the group consisting of chloramine T, a mixture of ascorbic acid and gentisic acid, and stannic chloride (II).
7. The method for preparing chitosan hydrogel-chelating agent labeled with radionuclide according to claim 1, wherein the chelating agent is a chelating agentWhen N-succinimidyl-3- (4-hydroxyphenyl) propionate is used, the radionuclide is selected from the group consisting of 131 I、 125 I and 124 1 or more of group I.
8. The method for preparing chitosan hydrogel-chelating agent labeled with radionuclide according to claim 1, wherein when the chelating agent is 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid, the radionuclide is 177 Lu。
9. The method of claim 1, wherein when the chelating agent is diethylenetriaminepentaacetic acid, the radionuclide is selected from the group consisting of 186 Re、 188 Re and 99m tc is used as a catalyst.
10. A chitosan hydrogel-chelator labeled with a radionuclide, prepared by the method of any one of claims 1 to 9.
11. A composition for cancer treatment comprising the chitosan hydrogel-chelating agent labeled with radionuclide according to claim 10.
12. The composition for cancer therapy according to claim 11, wherein said cancer is at least 1 selected from the group consisting of liver cancer, lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, cutaneous melanoma, uterine cancer, ovarian cancer, rectal cancer, large intestine cancer, colon cancer, breast cancer, uterine sarcoma, carcinoma of fallopian tubes, endometrial cancer, cervical cancer, vaginal cancer, vulva cancer, esophageal cancer, small intestine cancer, thyroid cancer, sarcoma of soft tissue, urinary tract cancer, penile cancer, prostate cancer, chronic or acute leukemia, juvenile solid tumor, differentiated lymphoma, bladder cancer, kidney cancer, renal cell carcinoma, renal pelvis cancer, first central nervous system lymphoma, cerebrospinal tumor, brain stem glioma and pituitary tumor.
13. The composition for cancer treatment according to claim 11, wherein the composition is in the form of an injection.
14. A pharmaceutical composition for treating embolism, comprising the chitosan hydrogel-chelating agent labeled with radionuclide according to claim 10 as an active ingredient.
15. The pharmaceutical composition for the treatment of embolism according to claim 14, wherein said composition is injected through the hepatic artery.
16. A method for preventing or treating cancer in a subject, comprising: a step of treating the chitosan hydrogel-chelating agent labeled with radionuclide described in claim 10 to a subject in need thereof.
17. A method for preventing or treating an embolism in a subject, comprising: a step of treating the chitosan hydrogel-chelating agent labeled with radionuclide described in claim 10 to a subject in need thereof.
18. Use of the chitosan hydrogel-chelator labeled with a radionuclide according to claim 10 for the preparation of a medicament for the treatment of an embolic disorder.
19. Use of the chitosan hydrogel-chelator labeled with a radionuclide according to claim 10 for the preparation of a medicament for the treatment of cancer.
20. A composition comprising the chitosan hydrogel-chelator labeled with a radionuclide according to claim 10, for use in cancer therapy.
21. A composition comprising the chitosan hydrogel-chelator labeled with a radionuclide according to claim 10, for use in the treatment of an embolism.
22. A chitosan hydrogel-chelator for labeling radionuclides, comprising:
a chitosan hydrogel in combination with a chelating agent having a functional group capable of labeling a radionuclide; and
a radionuclide linked to the functional group.
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